Pain - particularly chronic pain - is a major cause of morbidity, especially in patients with cancer or neuropathic pain. These conditions are often refractory to treatment. The purpose of this research is to develop microparticle based prolonged duration local anesthetics (PDLA) employing site 1 sodium channel blockers such as tetrodotoxin (TTX). The underlying hypothesis - which was validated in preceding research - is that TTX, encapsulated in combination with compounds such as conventional local anesthetics and steroids, can produce extremely long nerve blocks. As envisioned here, PDLA could last weeks to months for chronic pain, or could be tailored to shorter durations for other (e.g. perioperative) applications. The research could potentially be applicable to any excitable tissue (brain, muscle, heart, uterus), and in fact to any environment where controlled release could be useful. One specific aim of this research is to resolve difficult formulation problems such as burst release, which arise in encapsulating potentially toxic hydrophilic molecules. Microspheres of a-hydroxy ester polymers such as PLGA, containing TTX, bupivacaine, and dexamethasone will be modified sequentially as needed to minimize burst release and extend release in vitro. The spectrum of potential modifications includes constructing secondary polymeric shells, use of cross- linkable hyaluronic acids inside or outside of the particles, using alternative polymers such as polyanhydrides, and devising TTX-only systems, since TTX - unlike conventional local anesthetics - is not believed to cause myo- or neurotoxicity. An equally important aim will be the in vivo assessment of the efficacy and toxicity of these new formulations by neurobehavioral tests in rats and rabbits, and by following serum levels. Another crucial aspect of the research, which has not received sufficient attention, will be to understand of factors that contribute to the development of inflammation, myotoxicity, and neurotoxicity with PLDA formulations, and perhaps mitigating or avoiding those. [unreadable] [unreadable]